Chronic rejection, the major limitation of cardiac transplantation, is characterized by pathological remodeling[unreadable] and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly[unreadable] understood, but is likely immune-mediated and may result from chronic delayed-type hypersensitivity[unreadable] responses by recipient T cells to donor vascular antigens through the secretion of cytokines, such as[unreadable] interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an antiproliferative effect on vascular smooth muscle cells (VSMCs) and was considered to function as a proarteriosclerotic agent solely because[unreadable] of its immunomodulatory effects on endothelial cells and infiltrating leukocytes. However, we have found that[unreadable] IFN-gamma elicits arteriosclerosis in the absence of leukocytes. Our prior observations and current preliminary[unreadable] studies have led us to hypothesize that IFN-gamma induces VSMC proliferation that depends on a mTOR/p70S6K[unreadable] pathway, sensitizes VSMCs to apoptosis through upregulation of XAF1 and Noxa, and primes VSMCs for[unreadable] innate immune responses to fragmented nucleic acids by induction of RIG-I and MDA5. These disparate[unreadable] effects of IFN-gamma on VSMC survival and inflammation interact and cause intimal expansion, outward vascular[unreadable] remodeling, and vasodysfunction of conduit coronary arteries which ultimately determine lumen size and[unreadable] blood flow. We further hypothesize that these direct actions of IFN-gamma on VSMCs will be inhibited by[unreadable] peroxisome proliferator-activated receptor (PPAR)gamma ligands. To test our hypotheses with the experiments[unreadable] planned in this project, we have formed productive collaborations with other investigators of the program[unreadable] application and together we have developed novel models of GA in which human coronary arteries are[unreadable] interposed in severely immunodeficient mouse hosts that produce human IFN-gamma by adenoviral vector[unreadable] infection. Our methods are supplemented by mouse artery transplantation models and by cellular and[unreadable] molecular studies of human VSMCs. We will use these approaches to elucidate the effects of IFN-gamma on[unreadable] arterial tissue in vivo and in vitro. The outcomes of these studies will provide considerable new information[unreadable] about the role of IFN-gamma in GA, may identify novel therapeutic targets to treat and image GA, and investigate[unreadable] mechanisms of inhibiting GA by existing pharmacological agents.[unreadable]